Mechanisms of lincDUSP Oncogenic Effects in Colon Cancer

lincDUSP 对结肠癌的致癌作用机制

基本信息

批准号：
10232150
负责人：
Thomas Louis LaFramboise
金额：
$ 36.09万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10232150
关键词：
3-Dimensional Affect Apoptosis Automobile Driving Biological Markers Cancer Etiology Cells Cessation of life Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Colon Colon Carcinoma Colonic Neoplasms Complex DNA Data Disease Epithelial Gene Expression Gene Expression Regulation Genes Genomics Goals Health Human Immunodeficient Mouse KRAS2 gene Knock-out Laboratories Lead MADH4 gene Malignant Neoplasms Mediating Molecular Mutation NMR Spectroscopy Nuclear Oncogenes Oncogenic Organoids Patients Phenotype Play Process Proteins RNA RNA Binding RNA analysis Recurrence Role Site Structure TP53 gene Testing The Cancer Genome Atlas Tissues Treatment Failure Tumor Cell Line United States Untranslated RNA Up-Regulation Validation Work Xenograft Model Xenograft procedure base cancer cell cancer type chromatin isolation by RNA purification sequencing cohort colon cancer cell line colon tumorigenesis experimental study genome-wide genomic locus in vivo knock-down new therapeutic target novel novel therapeutics overexpression protein complex recruit targeted treatment transcriptome sequencing tumor tumor microenvironment

项目摘要

PI: Khalil, Ahmad Technical Abstract: Colon cancer is the second leading cause of cancer-related death in the United States, largely due to frequent treatment failure and recurrence. Recent studies, including work from our laboratory, have demonstrated that regulatory long intergenic non-coding RNAs (lincRNAs) are major players in the process of colon tumorigenesis, and could emerge as novel therapeutic targets. In this proposal, we have identified and functionally characterized a novel lincRNA, referred to as lincDUSP, that exerts an oncogenic effect in colon cancer cells. Knockdown of lincDUSP significantly abrogates the tumor phenotype, including decreased proliferation and colony formation, and increased apoptosis. These studies have also revealed that lincDUSP regulates numerous genes by directly interacting with chromatin, and potentially recruiting protein complexes to specific genomic loci. In aim 1 of this proposal, we will further test the oncogenic function of lincDUSP in vivo using a xenograft model, and also assess the role of lincDUSP in driving colon tumorigenesis using 3D organoids. In aim 2, we will investigate the molecular mechanisms of lincDUSP by assessing its role in gene regulation, and characterize the protein complexes that are required for lincDUSP oncogenic activity. Lastly, we will determine the secondary structure of lincDUSP that facilitates its interaction with DNA and proteins. The completion of the proposed studies could lead to establishing lincDUSP as a novel oncogenic lincRNA with direct impact on colon tumorigenesis, and possibly as a target for therapy.

PI：哈利勒，艾哈迈德技术摘要：结肠癌是美国癌症相关死亡的第二大原因，主要是由于经常治疗失败和复发。最近的研究，包括我们的工作实验室证明，调节性长基因间非编码 RNA (lincRNA) 结肠肿瘤发生过程中的主要参与者，并可能成为新的治疗方法目标。在这个提案中，我们鉴定了一种新型 lincRNA，并对其进行了功能表征，称为 lincDUSP，对结肠癌细胞产生致癌作用。击倒 lincDUSP 显着消除肿瘤表型，包括增殖减少和集落形成，并增加细胞凋亡。这些研究还表明 lincDUSP 通过直接与染色质相互作用来调节许多基因，并可能招募与特定基因组位点的蛋白质复合物。在本提案的目标 1 中，我们将进一步测试使用异种移植模型研究 lincDUSP 在体内的致癌功能，并评估 lincDUSP 使用 3D 类器官驱动结肠肿瘤发生。在目标 2 中，我们将调查通过评估 lincDUSP 在基因调控中的作用来研究 lincDUSP 的分子机制，并表征 lincDUSP 致癌活性所需的蛋白质复合物。最后，我们将确定 lincDUSP 的二级结构，促进其与 DNA 的相互作用蛋白质。拟议研究的完成可能会导致 lincDUSP 成为一种新颖的药物致癌 lincRNA 对结肠肿瘤发生有直接影响，并可能作为治疗。